Natural killer (NK) cells constitute 15% of peripheral blood lymphocytes and play an important role in the ability of the innate immune system to fight off viral infections and also cancer (see, e.g., Purdy A K et al., Cancer Biol Ther 2009; 8:13-22) and Vivier et al., Science 2011 Jan. 7; 331(6013):44-9). NK cells bind to target cells through multiple receptors, including natural cytotoxicity receptors (NCR), the Fc receptor CD16, NKG2D, and others. Binding of ligand to receptor initiates tyrosine phosphorylation and recruitment of accessory signaling molecules. This cascade results in activation of the NK cell, release of preformed granules containing perforin and granzymes into the target cell, and apoptosis. The concurrent release of cytokines and chemokines results in a micro-environmental milieu that recruits other immune cells. NK cells have the capability of binding every cell in the body (Murphy W J, et al., Biol Blood Marrow Transplant 2012; 18:S2-S7). However, binding of normal cells does not result in cytotoxic activity because of the ability of NK cells to simultaneously utilize a different set of receptors to bind major histocompatibility complex (MHC) class I molecules. Binding of human leukocyte antigen (HLA) E to the NKG2A/CD94 heterodimeric receptor, or of HLA-A, B and C molecules to inhibitory killer Ig-like receptors (KIRs), results in tyrosine phosphorylation, recruitment of the signaling adaptors SHP-1 or SHP-2, and downstream signaling. The end result is a dominant signal that suppresses normal activation signals. Thus, KIR/HLA interaction can impact NK cell responsiveness and also the development of the total number of mature responsive NK cells, known as licensing.
There are seven inhibitory KIRs and seven activating KIRs, which is one factor that results in diversity of KIR inheritance and expression. KIR is also expressed on natural killer T (NKT) cells and a small subset of T cells (Uhrberg M, et al., J. Immunol. 2001; 166:3923-3932). Thus, mechanistically, blockade of inhibitory KIR could induce anti-tumor effects by allowing for activation of NK cell and possibly also some T cells.
CS1 (also known as SLAMF7, SLAM Family Member 7, CD2 Subset, CRACC, CD2-Like Receptor-Activating Cytotoxic Cells, 19A24 Protein, 19A, CD2-Like Receptor Activating Cytotoxic Cells, CD319, Novel LY9 (Lymphocyte Antigen 9) Like Protein, Membrane Protein FOAP-12, CD319 Antigen, Protein 19A, APEX-1, FOAP12, and Novel Ly93) is a cell surface glycoprotein that is highly expressed on multiple myeloma (MM) cells. CS1 is expressed at high levels in normal and malignant plasma cells, but not normal organs, solid tumors, or CD34+ stem cells. Only a small subset of resting lymphocytes, including NK cells and a subset of CD8+ T cells, express detectable but low levels of CS1 (Hsi E D, et al., Clin. Cancer Res. 2008; 14:2775-2784 and Murphy J J, et al., Biochem J. 2002; 361:431-436). CS1 was isolated and cloned by Boles et al. (Immunogenetics. 2001; 52(3-4):302-7).
Multiple myeloma (also known as myeloma or plasma cell myeloma) is a hematological cancer formed by malignant plasma cells. Normal plasma cells are a type of white blood cell that are found in the bone marrow and make antibodies. MM is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal light chains). In MM, neoplastic plasma cells accumulate in the bone marrow and produce a monoclonal protein that causes organ and/or tissue impairment (Smith D, Yong K, BMJ. 2013 Jun. 26; 346: f3863). Common clinical manifestations of MM include hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, impaired production of normal immunoglobulin, and diffuse osteoporosis (usually in the pelvis, spine, ribs, and skull).
MM is the second most common (10-15% of all) hematological cancer. It is responsible for 15-20% of deaths from hematological cancer and about 2% of all deaths from cancer (Smith D, Yong K, BMJ. 2013 Jun. 26; 346:f3863). Despite advances in therapy, MM is still considered an incurable disease (Hsi E, et al., Clin. Cancer Res., May 1, 2008 14; 2775; Hari P, et al., Bone Marrow Transplant 2006; 37:1-18; Greipp P., Semin Hematol 2005; 42:S16-21; Crane E, List A., Cancer Invest 2005; 23:625-34; Gahrton G, et al. Hematology 2005; 10 Suppl 1:127-8; Anderson K C., Semin Hematol 2005; 42:S3-8). Accordingly, it is an object of the present invention to provide improved methods for treating subjects with MM.